Cooperative Suppression of Ovarian Cancer Growth by 1,25-Dihydroxyvitamin D3 and Sodium Selenite Mediated Through SEPP1 Induction.

Advanced epithelial ovarian cancer responds poorly to current treatments, creating an urgent need for novel therapeutic strategies. 1,25-dihydroxyvitamin D3 (1,25D3) exerts potent anti-proliferative effects on ovarian cancer cells in vitro, but the concentrations required for growth suppression in cell culture are not readily achievable in vivo, and higher doses induce hypercalcemia, which hinders its clinical translation. Sodium selenite (Na2SeO3) has been identified as a chemopreventive agent that inhibits the growth of multiple cancer types. In this study, we demonstrated that combined treatment with Na2SeO3 and 1,25D3 exerts enhanced anti-proliferative efficacy against ovarian cancer cells both in vitro and in vivo. Specifically, 1,25D3 upregulated the expression of vitamin D receptor (VDR) and Selenoprotein-P1 (SEPP1), and this effect was further enhanced by Na2SeO3 co-treatment. Consistently, Na2SeO3 augmented the suppressive effect of 1,25D3 on ovarian cancer cell proliferation, demonstrating synergistic inhibitory activity. Notably, knockout (KO) of either VDR or SEPP1 abrogated this synergistic effect. Mechanistic investigations confirmed that SEPP1 is a direct target gene of VDR, and functional vitamin D response elements (VDREs) are present within its genomic locus. In vivo, low-dose 1,25D3 (0.3 μg/kg) combined with Na2SeO3 outperformed 1,25D3 monotherapy, with no significant hypercalcemia, ascites formation, or metastasis observed throughout the treatment period. These findings indicate that Na2SeO3 acts in combination with 1,25D3 to induce SEPP1 expression, thereby enhancing the antitumor efficacy of low-dose 1,25D₃ against ovarian tumors. This study provides a promising strategy for the safe and effective application of 1,25D3 in ovarian cancer therapy.